N-(3-halo-2-hydroxypropyl)-p-aminobenzoate compounds



United States Patent N(3-HALO-2-HYDROXYPROPYL BENZOATE COMPO No Drawing.Application 0mm 30, 1952, Serial No. 317 813 8Claims. (Cl. 66-470)AMINO- Knlamam, Mich a This invention relates to certain newhalohydroxypropyl compounds and to a method for their preparation. Thisapplication is a continuation-in-part of application Serial No. 41,884,filed July 31, 1948, now United States Patent No. 2,629,733.

The compounds of the invention, herein defined as the N-(3 halo 2hydroxypropyl)-p-aminobenzoate compounds have the generic formulax-cmcnoncm-rzQco Nrrdncmomco on' III N- (3-hulo-2-hydroxypropyl) -paminobenzoate compound wherein R is a member of the group consisting ofhydrogen and the alkyl radicals, n is a member of the group consistingof zero and the positive integers 1 to 7, inclusive, Z is a member ofthe group consisting of hy- I Epihalohydrln COO-alkyl H-IIQC o Nndncmcmc07..0-alkyl II p-Amlnohenzoate compound COO-alkyl x-cmcnoncnrriOcoNndnomcmco oaum go III-E N- (3-halo-2-hydroxypropy1)paminobenzoatecompound (ester) Alkali, then acidification COOK- IV N-(2,3-epoxypropyl)-p-amlnobenzoate compound Kalamam, Martinsville, Va

' Patented Mar. 6, 1956 ice III-AN(3-halo-2-hydroxyprdpyl)-fi;.mlnobensoate compound no a \yjously, byreacting an epihalohydrin having the Formula epibromohydrin orepiiodohy- The N- I, i. e. epichlorohydrin, drin, with a p-aminobenzoatecompound (II).

(3-halo-Z-hydroxypropyl)-p-aminobenzoate compounds of the inventionwhich are acids (HI-A) can be prepared from the esters (III-E) by firstreacting them with an alkali to convert the 3-halo 2-hydroxypropylradical to the 2,3-epoxypropyl radical and hydrolyze the ester radicals,either simultaneously or sequentially, to form a salt of anN-(2,3-epoxypropy l)p-aminobenzoate compound (IV). The free acid can beliberated by acidification and, upon'reaction with a hydrogen halide, i.c. with hydrogen chloride, hydrogen bromide or hydrogen iodide, isconverted to the' acid N-(3-halo-2-hydroxypropyl)-paminobenzoatecompounds (HI-A).

In. the naming of compounds of the invention and of other compoundsmentioned herein when both a glutamic acid residue and a p-aminobenzoicacid residue are included in the molecule, the nitrogen atom of theglutamic acid residue is, for convenience, herein referred to by thesymbol N' and the nitrogen atom of the p-aminobenzoic acid nucleus isreferred to by the symbol N. In the structural formulae given herein,aromatic nuclei are represented by one or more simple hexagons.

The N-(3 halo 2 hydroxypropylFp-aminobenzoate compounds (III) arevaluable as intermediates in the preparation of other compounds which,in turn, are useful in the preparation of certain compounds referred tobroadly in the art as folic acids. Thus, as described and claimed inconcurrently filed co-pending application Serial No. 317,812, now U. S.Patent 2,673,861, which is a continuationin-part of the parentapplication, they can be converted readily toN-(2,3-epoxypropyl)-paminobenzoate compounds having the Formula IV givenpreviously herein which, as described and claimed in the parentapplication Serial No. 41,884, now U. S. Patent 2,629,733, are convertedreadily to N-(3-oxy-2-hydroxypropyl)-paminobenzoate compounds. Asdescribed in co-pending application Serial No. 41,889, now U. S. Patent2,625,562, and as claimed in concurrently filed copending applicationSerial No. 317,814, nowU. S. Patent 2,674,617, which is acontinuation-in-part thereof, diethylN-(N-(3wmethoxy-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)-glutamatecan be oxidized, e, g. with chromic acid, to form diethylN'-(N-(3-methbxy-Z-ketopropyD-N-(p toluenesulfonynpaminobenzoyl)-glutamate which can then be condensed with 2,4,5-triamino-G-hydroxypyrimidine, as described and claimed in U. S. Patent2,558,711,to form diethyl N'-(N((2- amino-4-hydroxy-6-pteridyD- methyl)-N -(p toluenesulfonyl)-p-aminobenzoyl)-glutamate. Upon treatment of thelatter compound with hydrogen bromide in an aliphatic acid medium tosplit the p-toluenesulfonyl radical from the molecule, and in thepresence of'a bromine acceptor to prevent bromination in the benzenenucleus prepared readily, as indicated in the accompanying 3 of theaminobenzoic acid residue according to the meth= od described andclaimed in U. S. Patent 2,562,222, and after subsequent hydrolysis ofthe ester groups,-there is formed N'-(N-((2-amino-4-hydroxy-6-pteridyl)methyl)'2-,4,5-triamino-6-hydroxypyrimidine to form the corresponding2-amino-4-hydroxy-6-pteridyl compounds and the latter then converted tocompounds of the folic acid type in the manner just described.

As indicated by the formula given, compounds containing more than oneglutamic acid or ester residue contem plated by the invention are thosewherein only the gamma-' carboxyl groups are involved in the peptidelinkages, such as the residues derived from N'-(p-aminobenzoyl)- gammaglutamylglutamic acid, N'-(p aminobenzoyl)-gamma-gintamyl-gamma-glutamylglutamic acid, and the like. Preferredcompounds of the invention are'those wherein n represents the integer 1,i. e. those containing one glutamic acid or esterresidue, and theinvention will be described with particular reference thereto.

Compounds similar to, or identical with, those of the folic acid groupmade by using compounds of the invention as intermediates, such aspteroylglutamic acid, which are of greatest value as measured by theirbiological activity against Lactobacillus and or Streptococcus fecalis'R., are those wherein the glutamicacid residues possess the sameconfiguration as l(+)-glutamic acid. However,

the invention also contemplates compounds having the dextroconfiguration as well as racemic mixtures.

Compounds wherein Z of the generic formula given represents anarylsulfonyl radical are of particular value because of the protectionafforded the aromatic amino group by the arylsulfonyl group. Compoundshaving the amino group thus protected are often not subject todecomposition and the formation of by-products when employed as areactant, e. g. when converted to the, 3- oxy-Z-hydroxypropyl compoundmentioned and oxidized with chromic acid, to nearly the same extent asare compounds in which the aromatic'amino group is unprotected.Following the carrying out of a reaction using a compound containingsuch an arylsulfonylamino group, the arylsulfonyl radical can be splitreadily from the molecule formed, as mentioned previously, by treatingthe compound with hydrogen bromide in an aliphatic acid medium and inthe presence of a bromine acceptor. By such treatment, the arylsulfonylradical is split from the molecule to give a high yield of the amine andbromination in the benzene nucleus is effectively prevented.

Although the invention will be described in the case of arylsulfonylcompounds with particular reference to p-toluenesulfonyl compounds, itis understood that the invention contemplates compounds containing otherarylshamans ing intermediate and final compounds prepared using startingcompounds wherein the arylsulfonyl group is replaced by analkylsulfonyl, aralkylsulfonyl or cycloalkylsulfonyl group, such as themethanesulfonyl, alpha-toluenesulfonyl or cyclohexylsulfonyl radicals,respectively. Although the benzoic acid ester or glutamic .acid esresidues present in the compounds of the invention can comprise anyalkyl ester, such as the methyl, ethyl, n-

.propyl, iso-propyl, n-b'utyl, amyl, lauryl, dodecyl and many otheresters, the preferred ester is' the ethyl ester due to matters ofconvenience and economy.

Although the invention is directed, particularly in case of esters ofthe glutamic acid residues,-to alkyl esters, the process of theinvention can also be carried out and correspon'ding'compounds preparedusing other esters, such as the phenyl, tolyl, xylyl, cyclohexyl, benzyland many other aryl, aralkyl or cycloalkyl esters.

The p-aminobenzoate compounds (II) used as starting materials can beobtained by the method described and claimed in part in -co-pendingapplication Serial No. 41,888. According to the method of the co-pendingapplication, a p-aminobenzoate compound having one glutamic acid residuein the molecule is prepared by reacting an alkyl ester of glutamic acidwith an N-(arylsulfonyl)- p-aminobenzoyl halide or with a p-nitrobenzoylhalide. The halides referred to in this connection are the chlorides'andthe bromides. When a p.-nitrobenzoyl halide is used, an ester ofN'-(p-nitrobenzoyl)-glutamic acid is first obtained which, uponreduction, e. g. with hydrogen using platinum oxide as a catalyst,yields an ester of N'- (p-aminobenzoyD-glutamic acid. The lattercompound can be converted readily by means of an arylsulfonyl halide toan ester of N'-(N-(arylsu1fonyl)-p-aminobenzoyl)-glutamic acid. When anN-(arylsulfonyl)-p-aminobenzoyl halide is reacted with an ester ofglutamic acid, an ester of N-(N-(arylsulfonyl)-p-aminobenzoyl)-glutamicacid is formed directly. The latter compound can, if desired, be treatedwith hydrogen bromide and a bromine acceptor, such as phenol, orcatechol, in an alisulfonyl radicals, such as the o-toluenesulfonyl,benzenesulfonyl, and naphthalene sulfonyl radicals as well as manyothers. Arylsulfonyl radicals having substituents, such as.

chlorine, bromine or a nitro group, on the aromatic nucleus can also beused provided only that the substituent is non-reactive under thereaction conditions. The preferred arylsulfonyl 'radical is thep-toluenesulfonyl radical because the compounds formed are generallywell defined crystalline solids and because it has been found thathigher yields of amines are often formed when splitting a'p-toluenesulfonylamino compound using hydrogen bromide than whensplitting certain other arylsulfonyl derivatives of the same aminocompound. It should be mentioned, furthermore, that the method involvedin the present invention can be carried out and the correspondphaticacid medium to split the arylsulfonyl radical from the molecule and forman N-(p-aminobenzoyl)-glutamic acid or its ester according to the methoddescribed and claimed in U. S. Patent 2,562,222, mentioned previously.Furthermore, the esters can be hydrolyzed to theN'-(paminobenzoyl)-glutamic and theN'-(N-(arylsulfonyl)-paminobenzoyl)-glutamic acids and these acids can,if desired, be reconverted to the corresponding alkyl esters, e. g. bytreatment with an alkanol and an esterification catalyst in knownmanner. In similar manner, other paminobenzoate compounds can beprepared having up to sevenglutamic acid residues in the molecule bystarting with the corresponding gamma-glutamylglutamic acids or esterscontaining the requisite number of peptide linkages.

The reaction of an epihalohydrin with a p-aminobenzoate compound can becarried out conveniently by heating a mixture of the substances,preferably with agitation and with the addition of a catalyticproportion of pyridine, quinoline, triethyl amine, tributyl amine orother tertiary amine to the mixture. A vigorous reaction generally takesplace upon the addition of the amine and after a short time the mixturecan be cooled and the excess.

P and the halogen compound and adding one chemically equivalentproportion of alkali slowly to the mixture so arm! or the like. In thecase of epoxy esters,

. A small sample of the solid solvents, such as alcohol or methyl ethylketone, can be included in the mixture to increase the solubility of thereactants, if desired. The use of more than about one chemicallyequivalent proportion of alkali is generally avoided except whereconcurrent hydrolysis of ester groups is desired. In the latterinstance, about one chemically equivalent proportion of alkali is alsoadded for each ester group present in the halogen compound. If desired,the epoxy esters can be recovered from the reaction mixture andsubsequently hydrolyzed with alkali to form the epoxy acids.

The formation of the epoxy compound is usually substantially completeafter for from about one-half to about one hour of refluxing, dependingupon the particular alkali used and the rate of addition thereof, andthe mixture can then be worked up in any appropriate manner to recoverthe epoxy compound. In the case of epoxy compounds which are acids, themixture can be poured into water and the epoxy acids, which are usuallywell defined crystalline solids, can be recovered by filtering and, ifdesired, purified by crystallizing from dilute ethwhich frequently areobtained as oily products, the epoxy compounds can be recovered byevaporating the mixture to dryness in vacuo, dissolving the residue inether and, after washing the ethereal solution with water or aqueoussodium bicarbonate to remove inorganic salts and acids,

volatilizing the ether.

The conversion of an N -(2,3-epoxypropyl)-p-aminobenzoate compound (1V)to an acid N-(3-halo-2-hydroxypropyl)-p-aminobenzoate compound (III-A)is effected, as mentioned previously, by treating the compound with ahydrogen halide, preferably in an anhydrous medium such as ether. Thereaction mixture is generally stirred at ordinary or slightly elevatedtemperatures for one or two hours during which time some of the productgenerally crystallizes unless a large excess of solvent is Example3.-N-(beta-naphthalenesulfonyl)-paminobenzoyl chloride One hundred ninegrams of N-(beta-naphthalenesulfonyl)-p-aminobenzoic acid was stirredwith three liters of toluene. One hundred ninety-six grants of thionylchloride was added over a 30 minute period and the mixture then refluxedfortwo hours. The hot solution was filtered and cooled and the crystalswhich separated were recovered by filtering. There were thus obtained101 grams of N-(beta-naphthalenesulfonyl)-p-aminobenzoyl chloridemelting at 128 degrees to 133 degrees C. Refrigeration and filtration ofthe mother liquor gave an additional 19.8 grams of crystals melting at130 degrees to 140 degrees C.

Example 4.Diamyl N-(N-(beta-naphthalenesulfonyl)-p-aminobenzoyl)-glutamate 'A mixture was prepared consisting of 50 gramsof N (beta-naphthalenesulfonyl)-p-aminobenzoyl chloride, 360 millilitersof ethylene dichloride and 55.7 grams of diamyl glutamate hydrogensulfate. The mixture was cooled to about 15 degrees C. and a solution of29.5 grams of triethylamine in 90 milliliters of ethylene dichloride wasadded over a 20 minute period while maintaining the temperature of themixture below about 20 degrees C. The mixture was stirred for about 1.5hours and then washed twice with 60 milliliter portions of water, oncewith 60 milliliters of 2 N hydrochloric acid, twice with 30 milliliterportions of saturated sodium bicarbonate solution, twice with 50milliliter portions of water and, finally, with 100 milliliters ofsaturated sodium chloride solution. The resulting product was dried withanused. Most of thesolvent can then be volatilized in vacuo and thecrystals recovered by filtering and drying. The acids are thusgenerally'obtained as crystalline solids having sharp melting points.

Certain advantages of the invention are apparent from the followingexamples which are given by way of illustration only and are not to beconstrued as limiting.

Example 1.- Ethyl N-(beta-naphthalenesulfonyl)-paminobenzoate Threehundred milliliters of pyridine was mixed with 165.2 grams of ethylp-aminobenzoate. The ester dis solved with the evolution of heat. Twohundred fortyeight grams of beta-naphthalenesulfonyl chloride wasstirred slowly into the mixture and stirring was continued for anadditional thirty-five minutes. The mixture was then cooled,stirred'with two liters of water and filtered. ethylN-(beta-naphthalene' sulfonyl)-p-aminobenzoate which was retained on thefilter was crystallized from ethyl Cellosolve. The crystallized productmelted at 188 degrees to 191 ,degrees C.

Example 2.-N-( beta-naph thalenesulfonyl) paminobenzoic acid thusobtained 300.4.

' for one-half hour.

hydrous sodium sulfate, filtered and the filtrate refrigerated overnight. The refrigerated solution was filtered and the small amount ofsolid material which had separated was discarded. The ethylenedichloride was volatilized in vacuo from the filtrate. One fourth of theresidue was set aside and the remainder was crystallized twice frommilliliter portions of alcohol. There was thus obtained 22.5 grams ofdiamyl N'-(N-(betanaphthalenesulfonyl) p aminobenzoyl)-glutamate.Repeated crystallization of the product from alcohol raised the meltingpoint to 123-1245 degrees C.

Example 5.- Diethyl N'-(N-(p-toluenesulfonyl)-paminobenzoyD-glutamate Amixture of 407 grams of N-(p-toluenesulfonyl)-paminobenzoic acid and3,450 milliliters of toluene was dried by distilling the mixture until350 milliliters of distillate had been collected. A few drops ofpyridine and 50 milliliters of thionyl-chloride was then added to thedry toluene solution and the mixture stirred and refluxed The solutionwas then cooled with agitation for 2 hours and the solid whichprecipitated was recovered by filtering and washing with toluene andthen .with mixed hexanes and drying. There was thus obtained 387 gramsof N-(p-toluenesulfonyl)-p-aminobenzoyl chloride melting at 141 degreesto 142 degrees C.

A mixture of 48 grams of diethyl l(+)-glutamate hy drochloride, 68 gramsof N-(p-toluenesulfonyl)-p-aminobenzoyl chloride, 19 grams of magnesiumoxide, 250 milliliters of ethylene dichloride and 100 milliliters ofwater was stirred with cooling for about 4 hours. The mixture wasfiltered and the. organic layer was separated from the filtrate andwashed successively with water, ice cold dilute hydrochloric acid, waterand dilute aqueous sodium bicarbonate. The washed organic layer was thendried and diluted with mixed hexanes until slightly turbid and allowedto crystallize. Upon filtering the mixture, there was obtained 78 gramsof diethyl N'-(N-(p-toluenesulfonyl)-p-aminobenzoyl)-l-glutamate meltingat 125 degrees to 126 degrees C. and having a specific rotation degreesin a mixture of 5 per cent methanol and 95 per cent of 95 per centethanol. The diester is hydrolyzed readily with dilute sodium hydroxideto form I zenesulfonyD-paminobenzoic acid and the diethyl l(+)-glutamate hydrochloride is replaced with a substantially equi-molarproportion of dibutyl glutamate hydrochloride. The employment ofN-(p-chlorobenzenesulfonyl)- p-aminobenzoic acid and dimethyl glutamatehydrochlon'de under similarcircumsta'nces leads to the formation ofdimethyl N'-'(N-(p-chlorobenzenesulfonyl)-p-aminobenzoyl)-glutamate.Hydrolysis of these esters with dilute sodium hydroxide givesN-(N-(benzenesulfonyl)- p-aminobenzoyl)-glutamic acid, andN'-(N-(p-chlorobenzenesulfonyl) p aminobenzoyl)-glutamic acid,respectively.

The employment of a substantially equi'molar propor- N (N (3 chloro 2hydroxypropyl) N (benzenesulfonyl) p aminobenzoyl) glutamate, diamyl N e(N (3 chloro 2 hydroxypropyl) N (naphthalene- 'sulfonyl) p aminobenzoyl)glutamate or dimethyl N (N (3 chloro 2 hydroxypropyl) N --(pchlorobenzenesulfonyl)-p-aminobenzoyl)-glutamate, respectively.

Example 8.--Ethyl N-(2,3-epoxypropyl)-N-(p-tolueitesulfonyl)-paminobenzoate Sufiicient per cent aqueous sodium hydroxide was i addeddrop-wise to a boiling alcoholic solution of ethyl tion of ethylN-(benzenesulfonyl)-paminobenzoate, ethyl N (naphthalenesulfonyl) paminobenzoate or of amyl N-(p-chlorobenzenesulfonyl)-p-aminobenzoate inplace of ethyl N-(p-toluenesulfonyl)-p-aminobenzoate in the foregoingprocedure leads to the formation of ethyl N (3 chloro 2 hydroxypropyl) N(benzenesulfonyl) p 3 aminobenzoate, ethyl N (3 chloro 2 hydroxypropyl)N (naphthalenesulfonyl) p aminobenzoate and amylN-(3-chloro-2-hydroxypropyl)-N-(pchlorobenzenesulfonyl) p aminobenzoate,respectively. The employment of a substantially equi-molar proportion ofepibromohydrin or of epiiodohydrin in place of the epichlorohydrinyields ethyl N-(3-bromo-2-hydroxypropyl) N (p toluenesulfonyl) paminobenzoate and ethyl N (3 iodo 2 hydroxypropyl) N (ptoluenesulfonyl)-p-aminobenzoate, respectively.

Example 7.-Diethyl N'-(N-(3-011loro-Z-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)glutamate A mixture of 2.85 gramsof diethyl N'-(N-(p-toluenesulfonyl) p aminobenzoyl) glutamate and 1.1grams of epichlorohydrin'was agitated at 135 degrees C. Two drops ofpyridine were added and agitation at 135 degrees C. was continued for 5minutes. The excess epichlorohydrin was volatilized under reducedpressure. The residue which consisted of diethylN-(N-(3-chloro-2-hydroxypropyl) N (p toluenesulfonyl) paminobenzoyl)-glutamate was used in subsequent experiments withoutfurther purification.

When epibromohydrin or epiiodohydrin is substituted in approximatelyequi-molar proportions for epichlorohydrin in the above procedure thereis produced diethyl N (N (3-- bromo 2 hydroxypropyl) N (ptoluene'sulfonyl) p aminobenzoyl) glutamate or diethyl N (N (3 iodo 2hydroxypropyl) N (P. toluenesulfonyl) p aminobenzoyl) glutamate,respectively. Also, by replacing the diethylN'-(N-(p-toluenesulfonyU-p-aminobenzoyl)-glutamate with an approximatelyequi-molar proportion of dibutyl N'-(N-(benzenesulfonyl) p aminobenzoyl)glutamate, diamyl N' )N- (naphthalenesulfonyl) p aminobenzoyl) glutamateor dimethyl N (N (p chlorobenzenesulfonyl) p N (3 chloro 2hydroxypropyl) N (p toluenesulfonyl)-p-aminobenzoate containing threedrops of t indicator solution to just maintain a permanent pink color.When no more alkali was'required, the solution was diluted with waterand filtered. There was thus obtained 4.1 grams of ethyl N-(2,3-epoxypropyl) N (p toluenesulfonyl) p' aminobenzoate as a residue meltingat 69 degrees to 71 degrees C. Upon recrystallization from diluteethanol, the compound melted at 7t degrees to 72 degrees C.

Analysis.-Calcd. for CmHmOsNS: C, 60.8;"H, 5.6; N, 3.7. Found: C,59.9;l1l, 5.8; N, 3.7.

In a similar manner the substitution of equi-molar proportions of ethylN-(3-chloro-2-hydroxypropyl)-N-(benzenesulfonyl) p aminobenzoate, ethylN (3 chloro- 2 hydroxypropyl) N (naphthalenesulfonyl) p-an1inobenz'oate, amyl N (3 chloro 2 hydroxypropyl) N (pchlorobenzenesulfonyl) p aminobenzoate, or

ethyl N 4 (3 bromo 2 hydroxypropyl) N (p toluenesulfonyl) paminobenzoatefor the ethyl N- (3.- chloro 2 hydroxypropyl) N (p toluenesulfonyl) paminobenzoate in the foregoing procedure leads to the formation of ethylN-(2,3-epoxypropyl)-N- (benzenesulfonyl) p aminobenzoate, ethyl. N (2,3epoxypropyl) N .(naphthalenesulfonyl) p aminobenzoate, amyl N (2,3epoxypropyl) N (p chlorobenzenesulfonyl) p aminobenzoate, or ethyl N(2,3- epoxypropyl) N (p toluenesulfonyl) p aminobenzoate, respectively.

Example 9.--N-(2,3-ep0xypropyl)-N-(p-toluenesulfonyl)-p-aminoberiz0icacid unreacted ester. The extracted solution was then acidifiedcarefully with dilute sulfuric acid and the mixture filtered. There wasthus obtained 3.69 grams ofN-(2,3-epoxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoic acid in theform of white crystals melting at degrees to. 119 degrees C. After onerecrystallization from dilute ethanol, the compound melted at 124degrees to 127 degrees C.

When the hydrolysis just described is carried out using; approximatelyequi-molar proportions of ethyl N-(2,3" epoxypropyl) N (benzenesulfonyl)p aminobenzoate, ethyl N-(2,3epoxypropyl -N-(naphthalenesulfonyl)-paminobenzoate or amyl N-(2,3-epoxypropyl)-N-(p-chlorobenzenesulfonyl)-p-aminobenzoate in place of the ethyl N (2,3epoxypropyl) N (p toluenesulfonyl) p aminobenzoate, there is obtainedN-(2,3-epoxypropyl)- N-(benzenesulfonyl)-p-aminobenzoic acid,N-(2,3-epoxypropyl)-N-(naphthalenesulfonyl)-p-aminobenzoic acid or N(2,3-epoxypropyl) N (p chlorobenzenesulfonyl) p-aminobenzoic acid,respectively.- 1

Example 10.-Dielhyl N N-(2,3-epoxypropyl)-N-(p-toluenesulfonyl)-p-amir|obenzoyl)-glutama!e A mixture consisting ofabout 1.3 grams of diethyl N (N (3 chloro 2 hydroxypropyl) N (ptoluenesulfonyl)-p-aminobenzoyl)-glutamate, 20 milliliters of methylethyl ketone, 0.17 gram of sodium bicarbonate and 3 milliliters of waterwas refluxed for 40 minutes. The methyl ethyl ketone and water were thendistilled in vacuo and the residue taken up in a mixture of ether andwater containing a small proportion of alcohol. The ether layer'wasseparated, washed with cold dilute sulphuric acid, then with water andsaturated sodium bicarbonate solution and, finally, twice with water andonce with saturated sodium chloride solution. The washed solution wasfiltered through anhydrous sodium sulfate and the ether distilled invacuo. The residue consisted of 098 gram of diethylN'-(N-(2,3-epoxypropyl)- N (p toluenesulfonyl) p aminobenzoyl) glutamatein the form of a light brown oil. This is a yield of 87.5 per cent ofthe theoretical amount.

When the above procedure was carried out using dilute ethanol instead ofmethyl ethyl ketone, there was obtained a 75 per cent yield of productwhich upon assay for epoxy content proved to be 80 per cent pure diethylN (N (2,3 epoxypropyl) N (p toluenesulfonyl) p-aminobenzoyl)-glutamate.

When the procedure was carried out using anhydrous potassium carbonateand anhydrous methyl ethyl ketone there was obtained a 72 per cent yieldof product which upon assay was found to contain 42.8 per cent ofdiethyl N (N (2,3 epoxypropyl) N (p toluenesulfonyl)p-aminobenzoyl)-glutamate.

Using the procedure of the first paragraph and substitutingapproximately equimolar quantities of dibutyl N (N (3 chloro 2hydroxypropyl) N (benzenesulfonyl)-p-aminobenzoyl)-glutamate, diamylN-(N-(3- chloro 2 hydroxypropyl) N (naphthalenesulfonyl)p-aminobenzoyl)glutamate, dimethyl N-(N-(3-chloro-2- hydroxypropyl) N (pchlorobenzenesulfonyl) p aminobenzoyl)-glutamate or diethylN-(N-(3bromo-2- hydroxypropyl) N (p toluenesulfonyl) paminobenzoyl)-glutamate for the diethyl N-(N-(3-chloro-2- hydroxypropyl)N (p toluenesulfonyl) p aminobenzoyl)-glutamate there is obtaineddibutyl N-(N-(2,3-epoxypropyl) N (benzenesulfonyl) p aminobenzoyl)glutamate, diamylN-(N-(2,3-epoxypropyl)-N-(naphthalenesulfonyl)-p-aminobenzoyl)glutamate,dimethyl N'- (N (2,3 epoxypropyl) N (p chlorobenzenesulfonyl)-p-aminobenzoyl)-glutamate or diethyl N-(N-(2,3- epoxypropyl) N (ptoluenesulfonyl) p aminobenzoyl)-glutamate, respectively. Hydrolysis ofthese epoxy esters substantially as by the method of Example 9 yields N(N (2,3 epoxypropyl) N (benzenesulfonyl)-p-aminobenzoyl)-glutamic acid,N'-(N-(2,3-epoxypropyl) N (naphthalenesulfonyl) p aminobenzoyl)-glutamicacid,N-(N-(2,3-epoxypropyl)-N-(p-chlorotoluenesulfonyl)-paminobenzoyl)-glutamicacid and N (N (2,3 epoxypropyl) N (p toluenesulfonyl)p-aminobenzoyl)-glutamic acid, respectively.

Example 11.-N-(3-chl0ro-2-hydr0xypropyl)-N-(p-tluenesulfonyl)-p-amin0benzoic acid glutamic acid,N-(N-(2,3-epoxypropyl)-N-(benzenesulfonyl)-p-aminobenzoyl)glutamic acid,N'(N-(2,3-epoxypropyl) N (beta naphthafenesulfonyl) paminobenchlorobenzenesulfonyl)-p-aminobenzoyl) glutamic acid yieldsN-(3-chloro-2-hydroxypropyl)-N-(benzenesulfonyl)-p-aminobenzoic acid,N-(3-chloro-2-hydroxypropyl)-N-(beta-naphthalenesulfonyl)-p-aminobenzoic acid, N- (3-chloro 2hydroxypropyl) N (p-chlorobenzenesulfonyl)-p-aminobenzoic acid,N-(N-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-amin0benzoyl)-glutamicacid, N'-(N-(3-chloro-2-hydroxypropyl)-N-(benzenesulfonyl)-p-aminobenzoyl)- glutamic acid, N'-(N-(3-chloro-2-hydroxypropyl)-N-(beta-naphthalenesulfonyl)-p-aminobenzoyl)-glutamicacid or N'-(N-(3-chloro-2-hydroxypropyl)-N-(pchlorobenzenesulfonyl)-p-aminobenzoyl)- glutamic acid, respectively.

The corresponding 3-bromo-2-hydroxypropyl and 3- iodo-2-hydroxypropylcompounds are prepared in entirely analogous fashion using a chemicallyequivalent proportion of hydrobromic acid or of hydroiodic acid in placeof hydrochloric acid.

-It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and

A solution of 2.01 grams of recrystallized N-(2,3-

epoxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoic acid in 30 millilitersof 0.57 normal hydrochloric acid in ether was stirred at roomtemperature for about two hours. Crystals separated from the mixtureduring the period of stirring. After removing most of the ether invacuo, the crystals were recovered by filtering and drying. There wasthus obtained 1.65 grams ofN-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoic acidin the form of crystals melting at 157 degrees to 161 degrees C.

Replacement of theN-(2,3-epoxypropyl)-N-(p-to1uenesulfonyl)-p-aminobenzoic acid in theforegoing procedure with an approximately equi-molar quantity-of N- (2,3epoxypropyl)-N-(benzenesulfonyl) -p-arninobenzoie acid,N-(2,3-epoxypropyl)-N-(beta-naphthalenesulfonyl)- p-aminobenzoic acid,N-(2,3-epoxypropyl)-N-(p-chlorobenzenesulfonyl) p aminobenzoic acid, N(N (2,3- epoxypropyl)-N-(p-toluenesulfonyl) p aminobenzoyl)- theinvention is, therefore, to be limited only by the scope' of theappended claims.

We claim:

1. The method which includes: heating a mixture comprising anepihalohydrin selected from the group consisting of epichlorohydrins,epibromohydrins and epiiodohydrins and a compound having the formulaCOO-alkyl wherein Z is a member of the group consisting of hydrogen andthe arylsulfonyl radicals and n is a member of the group consisting ofzero and the positive integer 1 to form a compound having the formulaCOO-alkyl X- C HzOHOHOHz-IIOO O (NHHCHzCHzC Ohio-alkyl wherein X is thehalogen of the epihalohydrin used;

2. The method of claim 1 wherein Z is an arylsulfonyl radical, n is theinteger 1 and X is chlorine.

3. The method which includes: heating a mixture comprisingepichlorohydrin and ethyl N-(p-toluenesulfonyl)- p-aminobenzoate to formethyl N-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyl)-p-aminobenzoate.

4. The method which includes: heating a mixture comprisingepichlorohydrin and diethylN-(N-(p-toluenesulfonyl)-p-aminobenzoyl)-glutarnate to form diethyl N-(N-(3-chloro-2-hydroxypropyl)-N(p aminobenzoyl)-glutamate.

5. A compound having the formula 'x-omononom-sr-Oo 0 (Naenomomc o)..0n'

wherein X is a halogen selected from the group consisting of chlorine,bromine and iodine, Z is a member of the group consisting of hydrogenand the arylsulfonyl radicals, n is a member of the group consisting ofzero and the positive integer 1 and R is a member of the groupconsisting of hydrogen and the alkyl radicals.

6. A compound as claimed in claim 5 wherein -X is chlorine, Z is anarylsulfonyl radical, n is the integer 1 and R is an alkyl radical.

7. EthylN-(3-chloro-2-hydroxypropyl)-N-(p-toluenesulfonyD-p-am'inobenzoate.

8. Diethyl N-(N-(3-chloro-2-hydroxypropyl) N(ptoluenesulfonyl)-p-aminobenzoyl)glutamate.

No references cited.

"- toluenesulfonyl)-p-

1. THE METHOD WHICH INCLUDES: HEATING A MIXTURE COMPRISING ANEPIHALOHYDRIN SELECTED FROM THE GROUP CONSISTING OF EPICHLOROHYDRINS,EPIBROMOHYDRINS AND EPIIODOHYDRINS AND A COMPOUND HAVING THE FORMULA 5.A COMPOUND HAVING THE FORMULA